Acyclic nucleotide analogues containing phosphonate groups are disclosed for example in U.S. Pat. Nos. 4,659,825, 4,808,716, 4,724,233, 5,142,051, 5,302,585, 5,208,221, 5,352,786, 5,356,886, in EP publication numbers 269,947, 481,214, 630,381, 369,409, 454,427, 468,119, 434,450, 618,214 and 398,231 and in WO 95/07920, WO 94/03467 and WO 96/33200. The teachings of these patents include compounds in which a phosphonate group is linked to a defined purine or pyrimidine base, generally at the 1- or 9-position of the pyrimidine or purine bases, respectively, by way of a 2-(methoxy)propyl group, a 2-(methoxy)ethyl group, a 2-methoxy-3-hydroxypropyl group, or a 2-methoxy-3-fluoropropyl group, known respectively as PMP, PME, HPMP and FPMP purine or pyrimidine compounds. These compounds exhibit antiviral and cytostatic activity.
Daluge et al. (34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Oct. 4-7, 1994) discloses carbovir derivatives in which the 6 position of the purine is substituted with cyclopropylamino, N-cyclopropyl-N-methylamino or N-aziridinyl.
Cihlar et al., xe2x80x9cAntimicrobial Agents and Chemotherapyxe2x80x9d 39(1):117-124 (1995) disclose N6-aminohexyl-PMEDAP.
Holy et al., xe2x80x9cACS Symp. Ser.xe2x80x9d 401:57-71 (1989) and Holy, xe2x80x9cKem. Ind.xe2x80x9d 38(10):457-462 (1989) describe the antiviral activity of certain N6-substituted nucleotide analogues.
Additional phosphonate-substituted pyrimidine analogues are disclosed by Holy et al., xe2x80x9cCollect. Czech. Chem. Commun.xe2x80x9d 64:242-256 (1999), Eger et al., xe2x80x9cJ. Med. Chem.xe2x80x9d 37:3057-3061 (1994), Wormstadt et al., xe2x80x9cJ. Heterocyclic Chem.xe2x80x9d 37:1187-1191 (2000), and Franchetti et al., xe2x80x9cNucleosides and Nucleotidesxe2x80x9d 14(3-5): 607-610 (1995). The latter three publications have a phosphonate-containing side-chain linked via a 6-N substituent of 2,4-disubstituted pyrimidine.
It is an object of this invention to provide compounds having antiviral activity, in particular against RNA or DNA viruses such as HIV, HBV or HSV.
It is an additional object to provide compounds useful in the preparation of ion exchange resins or chiral media.
It is a further object to provide intermediates and methods for making such compounds.
These and other objects will be more fully understood by further reference to the disclosures herein.
In accordance with the invention, novel compounds are provided having formula (I) 
where
R1 is H, amino or methylsulfanyl;
R2 is H, methyl, halo, xe2x80x94N(R5)2, hydroxy, protected hydroxy or a group of the formula (Ia) 
R3 is independently H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R4 is H or halo;
X independently is oxygen, sulfur or a bond;
Z independently is hydroxy, an ester or amide;
R5 is independently H, C1-C8 alkyl or a protecting group; and
* designates a chiral carbon atom; and
salts and solvates thereof.
The objects also are accomplished by a method for preparation of compounds of the formula (I) 
where
R1, R2, R3, R4, X, Z, R5 and * are defined above;
comprising reacting a compound of formula (II) 
where
R1 and R5 are defined above;
R2 is H, methyl, halo, xe2x80x94N(R5)2, hydroxy or protected hydroxy; and
X is O or S;
with a compound of the formula (III) 
where
Z is an ester or an amide;
* designates a chiral carbon atom;
R3 is H, methyl, halomethyl or protected hydroxymethyl; and
Y is a leaving group
in dipolar aprotic solvent in the presence of a base to obtain a compound of formula (I) where Z is ester or amide; (b) one or both Z groups optionally are converted to produce the compound of formula (I) where at least one Z is hydroxy.
In another embodiment of this invention, a method is provided for the preparation of compounds of formula (I) where
R1 is H, amino or methylsulfanyl;
R2 is xe2x80x94N(R5)2 
R3 is independently H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R4 is H or halo
X is oxygen or sulfur;
Z independently is hydroxy, an ester or amide;
R5 is independently H, C1-C8 alkyl or a protecting group; and
* designates a chiral carbon atom
comprising reacting a compound (IV) 
where
R3 is H, methyl, halomethyl or protected hydroxymethyl;
X is O or S; and
Z is amide or ester;
with N(R5)2. One or both Z groups optionally are converted to the compound of formula (I) where at least one Z is hydroxy.
In another embodiment, a method is provided for preparation of compounds of formula (V) 
where
R3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R5 independently is H, C1-C8 alkyl or a protecting group;
X is oxygen or sulfur;
Z independently is hydroxy, an ester or amide; and
* designates a chiral carbon atom;
comprising reacting compound (IVa) 
with N(R5)2 in anhydrous solvent, alkali hydroxide or alkali carbonate in aqueous solution and Z is optionally converted to the compound of formula (V) wherein 1 or 2 Z groups are hydroxy.
In another embodiment, a method is provided for the preparation of compounds of formula (VI) 
where
R1 is H, amino or methylsulfanyl;
R3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
Z independently is hydroxy, an ester or amide; and
* designates a chiral carbon atom;
comprising reacting a compound of formula (VII) 
where
R1 is H, amino or methylsulfanyl
with a compound of the formula (VIII) 
where Z is amide or ester in the presence of a base. Optionally one or both Z groups are converted to produce a hydroxy.
In another embodiment of this invention, a method is provided for the preparation of compounds of formula (XIII) 
where
R1 is H, amino or methylsulfanyl;
* is a chiral carbon atom;
R2 is H, chloro, hydroxy or amino;
R3 is H, methyl, halomethyl or hydroxymethyl; and
Z is amide or ester;
comprising (a) reacting a compound of the formula (IX) 
where
R1 is H, amino or methylsulfanyl;
R2 is H, chloro or amino;
with a compound of the formula (X) 
where
R3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
* is a chiral carbon atom;
R6 is hydroxy or protected hydroxy;
or R3 and R6 are joined by a cyclic acetal or ketal protecting group;
in the presence of a base without solvent or in the presence of an aprotic solvent to produce a compound of formula (XI) 
where
R1 is H, amino or methylsulfanyl;
* is a chiral carbon atom;
R2 is H, chloro or amino; and
R3 is H, methyl, halomethyl or protected hydroxymethyl; and
(b) reacting compound (XI) with a compound of the formula (XII)
Yxe2x80x94CH2P(O)(OZ)2xe2x80x83xe2x80x83(XII)
where
Y is a leaving group;
Z is amide or ester in the presence of a base in dimethylformamide or tetrahydrofurane to produce a compound of formula (XIII); and
(c) optionally hydrolyzing Z group in compound (XIII) to produce a compound of formula (VI) where 1 or 2 Z groups are hydroxy and X is oxygen atom.
In another embodiment of this invention, a method is provided for the preparation of compounds of formula (I) where
R1 is H, amino or methylsulfanyl;
R3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
R4 is halo;
X is oxygen;
Z independently is hydroxy, an ester or amide; and
* designates a chiral carbom atom;
comprising (a) reacting a compound of the formula (VI)
where
R1 is H, amino or methylsulfanyl;
R3 is H, methyl, hydroxymethyl, halomethyl or protected hydroxymethyl;
Z independently is an ester; and
* designates a chiral carbon atom;
with elemental halogen in an inert solvent to produce a compound of formula (I).
Optionally one or both Z groups are converted to hydroxy.
Further objects of this invention are accomplished by a method comprising administering a therapeutically effective amount of a compound of formula (I) to a patient in need of such treatment.